Survival advantage of heterozygous factor V Leiden carriers in murine sepsis

Abstract

Summary Background The high allelic frequency of the prothrombotic Leiden polymorphism in human blood coagulation factor V (fV) has been speculated to reflect positive selection during evolution. Heterozygous Leiden carriers enrolled in the placebo arm of the PROWESS sepsis trial, and heterozygous Leiden mice challenged with endotoxin both showed reduced mortality, whereas homozygous Leiden mice were not protected from lethal endotoxemia. Follow-up analyses of clinical outcomes, and of mouse models of infection with various pathogens remained inconclusive. Objective To establish whether aPC-resistance of fV Leiden modifies the outcome of bacterial infection in murine sepsis models. Methods Homozygous and heterozygous fV Leiden mice were subjected to gram-positive (S.aureus) or gram-negative (Y.pestis; E.coli) septic peritonitis, or polymicrobial, focal septic peritonitis induced by cecal ligation and puncture (CLP); and the effect of fV Leiden on 7-day survival and bacterial dissemination was assessed. Outcomes were compared to the sepsis survival of mice with genetically impaired hemostasis (hemophilia A, thrombocytopenia, thrombin receptor PAR4 deficiency, protein C receptor ProcR/EPCR-deficiency). Results Heterozygous, but not homozygous Leiden mice were protected from lethal infection with highly virulent S.aureus and Y.pestis strains. FV Leiden did not affect the outcome of sepsis induced by CLP, staphylokinase-deficient S.aureus, Pla-deficient Y.pestis, or E.coli. Thrombocytopenia, deficiency of PAR1 or PAR4 did not affect S.aureus sepsis survival, whereas hemophilia A increased mortality. ProcR-deficiency selectively abolished the survival advantage of heterozygous Leiden mice. Conclusions In mice, heterozygous fV Leiden carriers are protected from sepsis mortality after infection with clinically relevant human bacterial pathogens.

The coagulation system in host defense

“…Interestingly, Bastarache's group was not able to show that myeloid TF had any role in indirect lung injury during endotoxemia and CLP sepsis . In addition, the prothrombotic phenotype of FV Leiden heterozygosity in mice poses a survival advantage in endotoxemia and sepsis caused by S. aureus and Y. pestis but not by CLP or E. coli . The authors proposed that FV Leiden has anti‐fibrinolytic effects which opposes the bacterial fibrinolytic virulence factors .…”

“…In addition, the prothrombotic phenotype of FV Leiden heterozygosity in mice poses a survival advantage in endotoxemia and sepsis caused by S. aureus and Y. pestis but not by CLP or E. coli . The authors proposed that FV Leiden has anti‐fibrinolytic effects which opposes the bacterial fibrinolytic virulence factors . Interestingly, endothelial PC receptor deficiency but not PAR1 deficiency abrogated the survival advantage of heterozygous FV Leiden mice …”

Coagulation factor V mediates inhibition of tissue factor signaling by activated protein C in mice

“…Thus, aPC resistance of fV Leiden not only modifies the endogenous host response to infection with highly virulent bacterial pathogens such as S aureus and Y pestis 14 but also modulates the responsiveness to therapeutically administered aPC. The current findings could potentially explain why the beneficial effects of aPC resistance on infection and endotoxemia in mice (in the absence of aPC therapy) are limited to heterozygous fV Leiden mice, 13,14 because the antiinflammatory cofactor function of fV for endogenously formed aPC cannot be expressed in homozygous carriers. Of note, fV Leiden carriership had no effect on polymicrobial focal peritonitis or infection with E coli and attenuated strains of S aureus and Y pestis that lack virulence factors interacting with the host fibrinolytic system.…”

Factor V: an active player in inflammation

“…9,10 It remains to be investigated whether this fV-dependent aPC anti-inflammatory activity is disease context and pathogen specific. They also suggest that the fV-dependent inhibition of TF-EPCR-PAR2 signaling was not the only factor contributing to sepsis mortality reduction by aPC.…”

“…Many individual molecules have been identified lately that are pivotal for FL HSC self-renewal, 9,10 some of them also being important in adult HSCs. However, the challenging goal is now to understand their exact interplay and to find molecular patterns and hubs that can be used for regenerative approaches.…”